Clinicians often use opioids to treat patients with moderate-to-severe pain. Opioids, however, often result in side effects such as inducing or aggravating constipation as these drugs react at receptors outside the targeted central nervous system. Severe opioid-induced constipation may result in patient refusal to be treated with opioid therapy.
Opioid-induced constipation is predominantly mediated by gastrointestinal μ-opioid receptors as well as kappa receptors. Selective blockade of these peripheral receptors might relieve constipation without compromising centrally mediated effects of opioid analgesia or precipitating withdrawal.
Methylnaltrexone is a quaternary derivative of naltrexone and a peripherally-acting μ-opioid antagonist. It has restricted ability to cross the blood-brain barrier in humans because of its polarity and low lipid solubility. In healthy volunteers, intravenous or oral administration of methylnaltrexone was found to reverse opioid-induced reduction in bowel motility without affecting analgesia.
Methylnaltrexone and methylnaltrexone salts have poor absorption in the gastrointestinal system thereby rending orally administered methylnaltrexone with limited bioavailability.
Methylnaltrexone bromide is currently available as a subcutaneous injection to treat the side effects of opioid drug use, such as opioid-induced constipation. The dosage amount for the subcutaneous route is approximately 0.15 mg/kg while the oral route is approximately 3.2 mg/kg to 6.4 mg/kg, which is about twenty times higher than the subcutaneous route.
Thus, there remains a need in the art for formulations and methods of administering methylnaltrexone that will require lower doses compared to orally administered formulations and better patient compliance compared to subcutaneous and injectable formulations.